The approval of the first direct-acting antiviral agents (DAAs), the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek), have begun to usher in a new era of hepatitis C treatment. Until recently, most clinical trials have combined investigational DAAs with pegylated interferon/ribavirin standard therapy -- which has suboptimal effectiveness for hard-to-treat patients and causes side effects that lead many people to delay or refuse therapy -- but several teams are now reporting data from studies of all-oral, interferon-free regimens.

Kazuaki Chayama from Hiroshima University in Japan and colleagues conducted an open-label study to test Bristol-Meyers Squibb's daclatasvir plus asunaprevir for 24 weeks in people with null response to prior therapy with pegylated interferon/ribavirin with or without boceprevir or telaprevir (< 2 log reduction in HCV RNA). This lack of response is thought to be related to poor natural interferon responsiveness, which has been linked to IL28B gene pattern and black race/ethnicity. Null responders are particularly difficult-to-treat and urgently needs better therapeutic options.

Daclatasvir and asunaprevir have both shown good overall safety and antiviral potency in laboratory and early human studies, but higher doses of asunaprevir were discontinued to ALT elevation suggesting liver toxicity.

This ongoing study (AI447-017) began with a sentinel cohort of 10 prior null responder chronic hepatitis C patients. In contrast with most hepatitis C studies in the U.S. and Europe, a majority of the Japanese participants (60%) were women and the median age was higher, at 62 years. All had HCV genotype 1b, reflecting the distribution in the Japanese patient population; 20% had the favorable IL28B CC pattern and 80% had the intermediate CT pattern (none had TT).

Results

At week 4, 90% of participants had HCV RNA below the lower limit of quantification (LLOQ), though just 40% were undetectable.

Several participants had baseline viral mutations associated with resistance to daclatasvir (L28M, R30Q, L31M, Y93H) and some NS3 protease inhibitors (T54S, Q80L), but this did not appear to affect virological response.

Daclatasvir plus asunaprevirwas generally well-tolerated.

The most common adverse events were diarrhea (7 patients) and headache (4 patients).